Discovery of a Series of 5,11-Dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-ones as Selective PI3K-δ/γ Inhibitors

Fleur M. Ferguson, Jing Ni, Tinghu Zhang, Bethany Tesar, Taebo Sim, Nam Doo Kim, Xianming Deng, Jennifer R. Brown, Jean J. Zhao, Nathanael S. Gray

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Dual inhibition of PI3K-δ and PI3K-γ is an established therapeutic strategy for treatment of hematological malignancies. Reported molecules targeting PI3K-δ/γ selectively are chemically similar and based upon isoquinolin-1(2H)-one or quinazolin-4(3H)-one scaffolds. Here we report a chemically distinct series of potent, selective PI3K-δ/γ inhibitors based on a 5,11-dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-one scaffold with comparable biochemical potency and cellular effects on PI3K signaling. We envisage these molecules will provide useful leads for development of next-generation PI3K-δ/γ targeting therapeutics.

Original languageEnglish
Pages (from-to)908-912
Number of pages5
JournalACS Medicinal Chemistry Letters
Volume7
Issue number10
DOIs
Publication statusPublished - 2016 Oct 13

    Fingerprint

Keywords

  • kinase inhibitor
  • p110-γ
  • p110-δ
  • phosphatidylinositol-4,5-bisphosphate 3-kinase-delta
  • PI3K-γ
  • PI3K-δ

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

Cite this

Ferguson, F. M., Ni, J., Zhang, T., Tesar, B., Sim, T., Kim, N. D., Deng, X., Brown, J. R., Zhao, J. J., & Gray, N. S. (2016). Discovery of a Series of 5,11-Dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-ones as Selective PI3K-δ/γ Inhibitors. ACS Medicinal Chemistry Letters, 7(10), 908-912. https://doi.org/10.1021/acsmedchemlett.6b00209